The primary objectives of this study are to evaluate the efficacy of ascending doses of COR-003 in subjects with elevated levels of cortisol due to endogenous Cushing's Syndrome by assessment of reduction in Urinary Free Cortisol (UFC) concentrations and to identify the range of safe and effective doses of COR-003 that reduce mean UFC concentrations ≤ULN (upper limit of normal) of the assay at month 6 of the maintenance phase of dosing without a prior dose increase in that phase.

Male or female, ≥18 year of age, or of a minimal age as required by the local regulations with confirmed diagnosis of CS as defined according to the criteria in the guidelines for diagnosis of CS (Nieman 2008).

Drug: COR-003

Detailed Description:

This will be a single period, open-label, dose titration study to assess efficacy, safety, tolerability, and PK of COR-003 in subjects with CS. The trial design will identify both the minimally effective and maximally tolerated doses in this CS population. Following an initial screening period, this study will be conducted in 2 treatment phases as follows:

Dose titration phase: approximately 2 to 16 weeks to achieve an effective and tolerable maximum dose (the therapeutic dose)

Maintenance phase: 6 months of treatment at the therapeutic dose without a prior dose increase following the establishment of the appropriate dose identified in the titration phase;

Extended evaluation phase: 6 months of continued treatment after the maintenance phase (6 - 12 months); dose adjustments will be allowed as required for treatment

Efficacy will be assessed by measuring UFC concentrations at specified times as described in the clinical protocol.

Blood samples for the PK determination will be collected at the times indicated in the clinical protocol.

An independent Data Safety Monitoring Board (DSMB) will review the safety of the drug throughout the study. The constituents of the DSMB membership and a adjudication committee is specifically described in the clinical protocol.

Subjects completing the 6-month maintenance phase of the study will remain in the study for an additional 6 months for extended evaluations.

COR-003 will be provided under a compassionate use protocol for subjects who wish to continue treatment with COR-003.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Subjects eligible for enrollment in the study must meet all the following criteria:

Male or female ≥18 years of age

Able to provide written informed consent prior to any study procedures being performed; eligible subjects must be able to understand the informed consent form prior to inclusion into the study.

Confirmed diagnosis of newly diagnosed, persistent or recurrent CD if subjects are not candidates for surgery or radiotherapy CD is defined according to the criteria in the Endocrine Society Clinical Practice Guideline for diagnosis of CD (Nieman 2008). Previous medical records will be collected and used to support the diagnosis of CD.

Either MRI confirmation of pituitary macroadenoma, or inferior petrosal sinus gradient >3 after corticotropin-releasing hormone (CRH) stimulation for those patients with a microadenoma, or for subjects who have had prior pituitary surgery, histopathology confirming and ACTH-staining adenoma. If inferior petrosal sampling had been performed without CRH, then a central to peripheral pre-stimulation gradient >2 is required

Confirmed diagnosis of newly diagnosed, persistent or recurrent endogenous CS of other etiology if subjects are not candidates for surgery or radiotherapy. CS will be defined according to the criteria in the Endocrine Society Clinical Practice Guideline for diagnosis of CS (Nieman 2008). Previous medical records will be collected and used to support the diagnosis, and the differentiation of the cause of CS, specifically

Mean 24-hour UFC level of ≥1.5X ULN on repeated determination

Ectopic ACTH secretion, not of pituitary origin

Ectopic CRH secretion

Adrenal-dependent CS (adrenal adenoma, adrenal autonomy)

Etiology unknown

Subjects MUST have elevated mean 24-hour UFC levels ≥1.5X ULN of assay based on a minimum of four measurements from adequately collected urine. Urine may be collected on sequential days.

In addition to elevated mean UFC, presence of abnormal values from one of the following tests:

Abnormal DST: Elevated 8 AM serum cortisol ≥1.8 ug/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 PM the evening prior (if not conducted already in the diagnostic workup of the subject within the previous 2 months before start of Screening Phase; in that case previous test results and details of conduct will need to be available by the Baseline visit)

Previously irradiated subjects with CD or CS of other etiology will be allowed as long as the radiation treatment occurred > 4 years ago and subjects have not exhibited evidence for improvement in their underlying Cushing's disease for 6 months. The total number of previously irradiated subjects enrolled in this study will not exceed 10.

Subjects with CD or CS of other etiology who are not candidates for surgery, refuse surgery, or in whom surgery will be delayed for >6 months. Subjects may be allowed to participate in the trial while awaiting surgery, but must agree to complete this study prior to surgery. For subjects who have already undergone surgery, a minimum of 3 months should have elapsed before the subject can be deemed a surgical failure.

Subjects on treatment for CD or endogenous CS of other etiology for whom treatment has been inadequate or not well tolerated must agree to the following minimum washout periods prior to the Baseline Visit:

Subjects on megesterol acetate (medroxyprogesterone acetate) must agree to a washout period of at least 6 weeks prior to the Baseline Visit

A female is eligible to enter and participate in the study if she is of:

Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation.

Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age > 45 years, in the absence of hormone replacement therapy. However in questionable cases, a blood sample with FSH > 40MIU/ml and estradiol < 40pg/ml (<140 pmol/L) is confirmatory.

OR Child bearing potential and agrees to use highly effective methods of birth control while participating in the study and for 2 weeks after the study is completed.

Fertile men must also agree to use a medically acceptable form of birth control while on study drug and up to 2 weeks after the study is completed.

Able to comprehend and comply with procedures.

Exclusion Criteria

Subjects will be excluded from the study if any of the following criteria are met:

Subjects with Pseudo-Cushing's syndrome based on assessment of the investigator.

Subjects with cyclic Cushing's syndrome based on assessment of the investigator

Subjects with a non-endogenous source of hypercortisolism such as exogenous source of glucocorticoids or therapeutic use of ACTH.

Known inherited syndrome as the cause of hypercortisolism, including but not limited to multiple endocrine neoplasia Type 1, McCune Albright Syndrome and Carney Complex

Subjects with adrenal carcinoma

History of malignancy, other than thyroid, early stage prostate, squamous cell and basal cell carcinoma, within 3 years prior to the Screening Phase. Subjects with history of such allowed carcinoma must have a life expectancy of >1 year and must be on stable doses of their specific therapies. Subjects with early stage prostate cancer undergoing no treatment due to low grade potential may be enrolled.

Subjects with a history of Torsades des Pointes, or ventricular tachycardia, or ventricular fibrillation, or history of prolonged QT syndrome (including family history), or use of medications resulting in QT/QTc prolongation, or hypokalemia <3.0 meq/L.

History or symptoms of recurrent symptomatic cholelithiasis or pancreatitis.

Liver function tests (LFT) must not be above the following cut-offs during the Screening Phase:

ALT and/or AST >3 X ULN

Total bilirubin >2 X ULN If all LFTs are within normal limits (WNL) and total bilirubin (TBN) is elevated, examination of direct and indirect bilirubin may be conducted. Subjects with isolated indirect TBN up to 3X ULN are presumed to have Gilbert's syndrome and may be enrolled if all other LFTs are within normal levels.

History of documented or suspected drug-induced liver injury requiring drug discontinuation of ketoconazole or any azole antifungals.

Subjects with hypercholesterolemia who are currently treated with atorvastatin, lovastatin or simvastatin and not willing or unable to change to alternative therapies with pravastatin, fluvastatin, and rosuvastatin within 2 weeks of start of the Screening Phase.

Any other clinically significant medical condition, as determined by the Investigator that precludes enrollment and participation in the study through completion, including conditions that would preclude the subject from being able to follow instructions or to perform the necessary procedures (for example, psychiatric instability or severe disability).

Abnormal free T4. Subjects with TSH <LLN and normal free T4 are permitted to participate in the study.

Subjects who have a history of alcohol or drug abuse in the 6 month period prior to enrollment.

Subjects who have been treated with mitotane within 6 months of the Screening Phase.

Subjects who are currently taking any H2 receptor antagonists, proton-pump inhibitors, or sucralfate (all of which inhibit absorption of COR-003). A list of orally acceptable antacids (for example, Mylanta and Maalox) will be provided, and can only be taken a minimum of 2 hours after dosing of COR-003.

Subjects who receive any prohibited concomitant medication:

Weight loss medications (prescription or over the counter)

Acetaminophen >3 g total daily dose (due to increased hepatotoxicity)

Co-administration of strong inducers or inhibitors of CYP3A4 enzyme system that may interfere with the metabolism of COR-003 and cannot be discontinued prior to first dose

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01838551